Mutations to the family of nuclear and steroid hormone receptors are associated with a family of human genetic diseases and cancers such as rickets and resistance to thyroid hormone (RTH) as well as thyroid and prostate cancer. For certain mutations that directly affect hormone binding, we have shown that synthetic hormone analogs can be designed to rescue activity (potency and efficacy) to these otherwise functionally impaired proteins. These "molecular complements" may serve as a novel approach to the treatment of at least a subset of patients with these genetic disorders. In this proposal we will work to expand the scope of mutations that can be complemented by small molecules beyond mutations that solely effect ligand binding. We will focus on thyroid hormone receptor (TR) mutations associated with RTH, pituitary and thyroid cancer as well as mutations in the androgen receptor associated with androgen- independent prostate cancer. Particular emphasis is placed on mutations that are most prevalent in the population. We will (1) explore RTH and cancer associated mutations of TR that directly affect the ligand- dependent transactivation mechanism of nuclear receptors; (2) explore the use of hormone-activation domain conjugates to complement RTH and cancer associated mutations of TR that are remote to the hormone binding-site; (3) Develop a novel class of mutant targeting thyroid hormone PROTACS (PROteolysis TArgeting Chimeric molecules) as a novel strategy to releasing the dominant negative actions of RTH-associated TR mutations; (4) develop analogs of the anti-androgen bicalutamide to restore antagonist activity towards mutant ARs that confer androgen independence in prostate cancer. (5) Through this program we have identified estrogen analogs that uniquely activate mutant forms of the estrogen receptor (ER). We will further develop these "functionally orthogonal" estrogen/ER pairs as novel chemical biology tools for dissecting the seven or more estrogen dependent signaling pathways.